PROJECT SUMMARY The goal of the proposed study is to identify and determine the function of circular RNAs (circRNAs) in innate immunity and neuro-development. Appropriate activation of the immune response is crucial for host fitness. While effective control of invading pathogens or response to endogenous stress signals depend on rapid and robust induction of immunity signaling pathways, prolonged or aberrant activation, either systemically or locally, can lead to pathological conditions such as autoimmunity, cancer and neurodegeneration. In particular, chronic inflammation in the brain is associated with impaired neuro-development and function. Thus both the magnitude and duration of the immune response need to be tightly regulated. Non-coding RNAs (ncRNAs) play a critical role in modulating antiviral immunity in a wide variety of organisms. Recent advances in deep-sequencing technology and computational biology have greatly expanded the repertoire of regulatory ncRNAs, and circRNAs are the latest addition. Besides their unique configurations, circRNAs are distinct from their canonical linear siblings by harboring frequent exon scrambling events. Originally viewed as merely by-products of rare ?head-to-tail? back-splicing events, circRNAs have recently been characterized as an abundant class of RNAs in eukaryotes. However, with the exception of only a handful of circRNAs, the function of the vast majority is unknown. We identified a collection of circRNAs in Drosophila that are differentially expressed in response to bacterial infection, and our preliminary studies have implicated the brain-enriched circRNA Edis in innate immunity and neuro- development. We hypothesize that Edis modulates innate immunity signaling and neuro-development and function, and propose to employ a combination of genomic, computational, genetic, and biochemical approaches to establish the function of Edis and elucidate the regulatory mechanism underlying Edis expression. Completion of the proposed study will establish circRNAs as a new class of regulatory ncRNAs, elucidate the regulatory mechanism of circRNA expression, and determine their function in modulating innate immunity and neuro-development. This will advance our understanding of their evolutionarily conserved mammalian counterparts, and provide new insights into the mechanisms underlying the interplay between innate immunity and neuro-development in physiological and pathological settings.